Evolution has shaped all organisms to adapt to the day-night cycle generated by the rotation of the earth on its axis. This system consists of an internal clock, whose molecular components drive changes in organism behavior, metabolism, and the immune system, thus contributing to maintain body homeostasis. Many immune functions are known to follow a circadian rhythm of activity, including the expression of several cytokines, the number of lymphocytes, and the activity of phagocytic cells. In addition, a variety of chronic inflammatory diseases, from rheumatic arthritis to obesity, have been linked to altered circadian regulation and clock dysregulation is coupled to sickness behavior syndrome associated with most of the autoimmune and infectious diseases. While these studies underline the importance of the circadian clock in regulating immune functions and inflammation, the role of the circadian clock in the regulation of the host response to infection is not known. The primary objective of this proposal is to begin filling this key gap of knowledge by investigating the role of the circadian clock machinery in the regulation of the host response to infection. Our central hypothesis is that the circadian clock machinery regulates the host response to infection, and contributes to determine the severity and outcome of disease. Our long-range goal is to find new avenues to control infection and determine whether therapeutic and preventive strategies may be more effective at specific times of the day, setting up the basis for chronopharmacological intervention. We plan to test our hypothesis and fulfill the objectives of this application by pursuing the following Specific Aims: (I) Determine the role of the circadian clock in the regulation of the host response to infection. (II) Investigate the molecular mechanism by which the circadian clock regulates the expression of antimicrobial host defenses during infection.